This renewal of the program project Modulation of biodefense responses to microbial pathogens is composed of four projects and three cores focused on the immune response to Category B and C Biodefense Pathogens and their products. The central hypothesis is that early events during activation of the mucosal innate and adaptive immune responses determine whether or not immunity or injury is induced in response to infection, or bacterial toxin exposure, respectively. Each project focuses on a unique aspect of the theme to advance our overall understanding of the mucosal immune response to infectious agents or their toxins. Since human disease can be easily spread by deliberate or accidental contamination of food, water, or air, our focus is on mucosal tissues at the interface with environmental exposure. Project 1 (Lefrancois) proposes to investigate the mechanisms regulating the intestinal mucosal T cell response to oral Listeria monocytogenes infection (LM). A novel system that mimics human infection will be employed. Project 2 (McSorley) will examine a new model of relapsing Salmonella infection and will define the critical requirements to elicit protective immunity. Project 3 (Vella) will determine how pulmonary administration of Staphylococcus aureus enterotoxin mediates acute lung injury. An innovative proteomic mining strategy will be used to test the novel hypothesis that T cell responses against enterotoxins guide a cell damage process that manifests in profound lung pathology. Project 4 (Cauley) will investigate the mechanisms that support sustained cellular immunity in the lungs against influenza virus infection. The projects utilize in vivo models, in-depth cellular immunological techniques and state-of-the-art imaging and are supported by 3 cores: administrative, flow cytometry and fluorescence microscopy. The projects and cores synergistically interact and mutually reinforce one another to achieve the goals of the program. Coupled with strong institutional support, it is anticipated that significant new insights in immune response regulatio to pathogens and their byproducts will continue to be obtained.